Despite recent advances in prevention and management of heart disease, death due to chronic heart failure (HF) continues to rise worldwide and new treatments are needed (Thomas, S. et al. Heart Fail Clin 3:381-387 2007; Kaye, D. M. et al. Nat Rev Drug Disc 6:127-129 2007).
Aldosterone is one of a number of hormones with detrimental effects to the myocardium, whose circulating levels are elevated in chronic heart failure (Weber, K. T. New England Journal of Medicine 345:1689-1697 2001) and during progression of the post-myocardial (MI) heart to heart failure. Aldosterone can contribute significantly to the morbidity and mortality of heart failure (Weber, K. T. New England Journal of Medicine 345:1689-1697 2001; Connel, J. M. et al. Journal of Endocrinology 186:1-20 2005; Marney, A. M. et al. Clin Sci (Lond) 113:267-278 2007). It has severely detrimental effects on the post-MI and failing myocardium, both indirect (i.e. via elevating blood pressure, enhancing sodium retention, etc.) and direct (i.e. promotion of cardiac adverse remodeling, such as cardiac fibrosis, maladaptive hypertrophy, inflammation, oxidative stress, progressive loss of cardiac function and performance etc.). (Weber, K. T. New England Journal of Medicine 345:1689-1697 2001; Connel, J. M. et al. Journal of Endocrinology 186:1-20 2005; Marney, A. M. et al. Clin Sci (Lond) 113:267-278 2007; Zhao, W. et al. Am J Physiol Heart Circ Physiol 291:H336-343 2006). Accordingly, plasma aldosterone levels are a marker of heart failure severity (Swedburg, K. et al. CONSENSUS Trial Study Group. Circ 82:1730-1736 1990; Rouleau, J. L. et al. J Am Coll Cardiol 24:583-591 1994) and aldosterone antagonists, such as spironolactone and eplerenone, have well-documented beneficial effects in heart failure constituting a significant segment of the chronic HF pharmacotherapeutic regimen (Pitt, B. et al. New England Journal of Medicine 348:1309-1321 2003; Pitt, B. et al. New England Journal of Medicine 341:709-717 1999).
Aldosterone is a mineralocorticoid produced and secreted by the cells of the zona glomerulosa of the adrenal cortex in response to either elevated serum potassium levels or to angiotensin II (AngII) acting through its type 1 receptors (AT1Rs), endogenously expressed in the adrenocortical zona glomerulosa (AZG) cells (Ganguly, A. et al. Pharmacol Rev 46:417-447 1994). AT1Rs belong to the superfamily of G protein coupled receptors (GPCRs), and, upon agonist activation, couple to the Gq/11 family of G proteins (De Gasparo, M. et al. Pharmacol Rev 52:415-472 2000). Over the past few years, a number of GPCRs, including the ATiRs, have been shown to also signal through G protein-independent pathways (DeGasparo, M. et al. Pharmacol Rev 52:415-472 2000; Oro, C. et al. Pharmacol Ther 113:210-226 2007). The protein scaffolding actions of β-arrestin 1 and 2 (βaa1 and 2, also known as arrestins 2 and 3, respectively), universal receptor adapter/scaffolding proteins originally discovered as terminators of GPCR signaling, play a central role in mediating this G protein-independent signal transduction (Lefkowitz, R. J. et al. Science 308:512-517 2005; DeWire, S. M. et al. Annu Rev Physiol 69:483-510 2007).
The β-arrestin 1 (βarr1) protein regulates the function of the angiotensin II (Ang II) type 1 receptors (AT1Rs) and elicits aldosterone production in response to activation by Ang II in vitro and physiologically in vivo. Normally, the AT1R produces aldosterone through activation of G-proteins, which is blocked by Paul. Paul, after terminating G-protein activation by the AT1R, is capable of signaling to aldosterone production. Thus, βarr1 also results in sustained aldosterone production by Ang II in the adrenal cortex.
Accordingly, lowering aldosterone levels via adrenal βarr1 inhibition could be of enormous therapeutic benefit in post-myocardial infarction (MI) and chronic heart failure.